Inflammatory bowel disease (IBD) affects more than 1.4 million people in the United States and accounts for more than $1.7 billion dollars in health care costs. IBD requires lifetime care and currently has no medical cure. Therefore, understanding the mechanisms involved in the pathogenesis of IBD is crucial for developing new therapeutic strategies to prevent or cure this inflammatory disease. Current studies demonstrate a crucial role for Toll-like receptors and NF?B signaling in the pathogenesis of intestinal inflammation. In this context, our laboratory recently identified GPCR kinase-5 to be an important regulator of NF?B signaling in immune cells, especially macrophages. G-protein coupled receptor (GPCR) kinases originally discovered for their role in GPCR phosphorylation, are now known to also mediate signal transduction from non-GPCRs via phosphorylation of cytosolic substrates. Of the seven GRK family members (serine/threonine kinases), studies from our laboratory and others demonstrate an evolutionarily conserved role for GPCR kinase-5 (GRK5) in the regulation of NF?B signaling pathway, as well as in the consequent inflammatory disease pathogenesis, especially mediated by TLRs. Our published and preliminary results demonstrate that GRK5 plays an important role in mouse models of inflammation including colitis. The objective of this proposal is to further expand on our findings and examine the role o GRK5 in mouse models of intestinal inflammation and determine the cellular and molecular mechanisms by which GRK5 modulates inflammatory bowel disease. To accomplish our objective, we will examine the following specific aims: 1. Determine the in vivo mechanisms by which GRK5 regulates inflammatory bowel disease; 2. Determine the cellular and molecular mechanisms by which GRK5 regulates intestinal inflammation. Results from these proposed studies in the short-term will provide important insights into the role of GRK5 in the pathogenesis of inflammatory bowel disease (IBD). In the long-term our studies will contribute to identifying new and novel therapeutic targets for inflammatory diseases including IBD.